The present invention pertains to a drug delivery system suitable for oral administration that facilitates a pulsatile release of the active agent. A key aspect of the present invention is the discovery that a tablet with an immediate-release compartment, which contains a compressed blend of an active agent and one or more polymers, substantially enveloped by an extended-release compartment, which contains a compressed blend of the active agent and hydrophilic and hydrophobic polymers, can provide a substantially first order delivery of the active agent, interrupted by a timed, pulsed delivery of a preferably increased amount of the active agent. With respect to drugs subject to xe2x80x9cfirst passxe2x80x9d clearance, sustained drug delivery can be achieved through the present invention via an optional instant-release compartment, which provides a dose sufficient to exceed the liver""s metabolic capacity and to maintain therapeutic levels, preferably throughout a 24-hour period.
Drug efficacy generally depends upon the ability of the drug to reach its target in sufficient quantity to maintain therapeutic levels for the desired time period. The pulsatile release of an active agent is desirable when treating diseases that require drug delivery in a manner to maintain therapeutic levels notwithstanding circadian rhythms. Diseases that benefit from pulsatile drug delivery include angina, for example, which occurs with repeatable regularity at the end of the night and in the early morning hours while the patient is still asleep, and rheumatic diseases such as rheumatoid arthritis, the symptoms of which manifest during the night and into the beginning of the next day.
With traditional extended-release dosage formulations, which exhibit first order release rates, the efficacy of the active agent diminishes at the end of the night and the beginning of the next day. Therefore, a bolus or burst delivery of the active agent during this waning period can improve drug efficacy.
In addition, orally administered drugs must overcome several obstacles to reach their desired targets. Before orally administered drugs enter the general circulation of the human body, they are absorbed into the capillaries and veins of the upper gastrointestinal tract and are transported by the portal vein to the liver. The pH and enzymatic activities found in gastrointestinal fluids may inactivate the drug or cause the drug to dissolve poorly. Following their absorption in the intestine, certain orally administered drugs can be subject to a xe2x80x9cfirst passxe2x80x9dclearance by the liver and excreted into bile or converted into pharmacologically inactive metabolites. Decreased bioavailability of orally administered drugs can be a consequence of this first pass effect. A first pass effect is characterized by the liver removing a drug from the bloodstream prior to entering a patient""s general circulation. A drug can overcome a first pass if it is present in a sufficient quantity which exceeds the excretory or metabolic capability of the liver.
Orally administered drugs subject to the first pass effect generally exhibit nonlinear pharmacokinetics. Until the liver""s metabolic capacity has been exceeded, the amount of such drugs in the bloodstream is significantly lower than the amount administered. This metabolic elimination of the given dose results in reduced bioavailability. However, once the administered dose exceeds the liver""s metabolic capacity, a significant increase in the drug concentration in the bloodstream may be obtained. The first pass phenomenon presents particular difficulties in the maintenance of therapeutic levels of an orally administered drug over an extended period such as 12 or 24 hours.
Drug delivery systems that have evolved with respect to orally administered drugs subject to the first pass effect include formulations capable of immediate drug release that are suitable for administration from 3-4 times daily, and formulations capable of immediate and sustained drug release that are suitable for once-daily administration. The second type of formulation is preferred because patient compliance with prescribed drug regimens involving once-daily administration is substantially higher than those involving multiple administrations. A sustained release formulation, however, may subject the patient to toxic drug levels over part of the dosing period and sub-therapeutic drug levels over other portions of the dosing period, if the drug release does not occur at appropriate time intervals. The maintenance of therapeutic levels of an orally administered drug over an extended period thus depends upon a drug delivery system capable of providing an appropriate release pattern.
A valuable contribution to the art therefore would be the development of a drug delivery system in a single tablet formulation suitable for oral administration that facilitates a substantially first order delivery of the active agent, interrupted by a timed, pulsed delivery of a preferably increased amount of the active agent, and where the active agent is subject to xe2x80x9cfirst passxe2x80x9d clearance, can provide sustained drug delivery, preferably over a 24-hour period, by a dose sufficient to exceed the liver""s metabolic capacity and to maintain therapeutic levels.
Accordingly, an objective of the present invention is a single orally administrable tablet that can provide a substantially first order delivery of the active agent, interrupted by a timed, pulsed delivery of an increased amount of the active agent. A second objective of the present invention is a single orally administrable tablet that can overcome the xe2x80x9cfirst passxe2x80x9d effect by providing an instant-release dosage sufficient to exceed the liver""s metabolic capacity, and then continue to maintain therapeutic drug levels, preferably over a 24-hour period. A further objective of the present invention is a method for preparing a single orally administrable tablet that can provide a substantially first order delivery of the active agent, interrupted by a timed, pulsed delivery of a preferably increased amount of the active agent.
In a preferred embodiment of the invention, these and other objectives can be accomplished through a drug delivery system suitable for oral administration with an immediate-release compartment, which contains a compressed blend of an active agent and one or more polymers, substantially enveloped by an extended-release compartment, which contains a compressed blend of the active agent and hydrophilic and hydrophobic polymers, and substantially enveloped by an optional instant-release compartment, which provides a dose sufficient to exceed the liver""s metabolic capacity and to maintain therapeutic levels, preferably throughout a 24-hour period.
In a preferred embodiment of the present invention, the active agent in the extended-release compartment can diffuse out first, resulting in a first order release rate. As the active agent and soluble polymers in the extended-release compartment disintegrate, water will penetrate through the extended-release compartment and cause the immediate-release compartment to expand, creating a bursting effect that further disrupts any remaining integrity of the extended-release compartment. Where an optional inert core (i.e., a core containing one or more polymers without active agent) is present, its swelling in response to the water influx described above can also contribute to a bursting effect. The respective time periods for the dissolution of the active agent, and the bursting effect, can be regulated by varying the composition and relative amounts of the polymers in the compartments.
The extended-release compartment preferably comprises a combination of hydrophilic and hydrophobic polymers. In this embodiment, once administered, the hydrophilic polymer dissolves away to weaken the structure of the extended-release compartment, and the hydrophobic polymer retards the water penetration and helps to maintain the shape of the drug delivery system. The immediate-release compartment preferably comprises a compressed blend of active agent and one or more polymers with disintegration characteristics, which upon exposure to the aqueous medium, would burst to further break apart the already weakened extended-release compartment and provide preferably complete drug release. In another embodiment, the immediate-release drug compartment and the combination of hydrophilic and hydrophobic polymers in the extended-release drug compartment can be modified so the second peak does not result in a burst. Instead, the second peak can be tailored to be completed in a desired time interval, for example, 30 minutes to 12 hours after release of active agent from the extended-release compartment.
In another embodiment, the extended-release compartment can be inert (i.e., containing a combination of hydrophilic and hydrophobic polymers without active agent), which may be preferable where delayed drug release is necessary or convenient. For example, if orally administered before bedtime, this drug delivery system could deliver its active agent while the patient is asleep to facilitate optimal therapeutic drug levels just prior to awakening.
In a preferred embodiment, the active agent is a drug, which may be a therapeutic drug or a prophylactic drug. In another preferred embodiment, the drug can be diltiazem, trapidil, urapidil, benziodarone, dipyridamole, isosorbide mononitrate, or lidoflazine. In yet another, the drug can be a non-steroidal antiinflammatory drug (NSAID) or a steroidal antiinflammatory drugs, which includes diclofenac sodium, ibuprofen, ketoprofen, diflunisal, piroxicam, motrin, and naproxen.
In still another preferred embodiment, the active agent can be one or more drugs selected from acetaminophen, aldosterone, alprenolol, amitryptyline, aspirin, beclomethasone, diproprionate, bromocriptine, bupropion, butorphanol tartrate, carbidopa, cetirizine, chlormethiazole, chlorpheniramine, chlorpromazine HCl, cimetidine, clarithromycin, codeine, cortisone, cyclobenzamine HCl, desmethylimipramine, dextropropoxyphene, dihydroergotamine, diltiazem FIG, dobutamine HCl, divalproex sodium, domperidone, dopamine HCl, doxazosine, doxepin HCl, epinephrine, ergoloid mesylates, ergotamine tartrate estradiol, ethinylestradiol, fenofibrate, fexofenadine, flunisolide, fluorouracil, flurazepam HCl, 5-fluoro-21-deoxyuridine, furosemide, glipizide, glyburide, glyceryl trinitrate, guanethidine sulfate, hydralazine HCl, imipramine HCl, indoramin, isoethorine HCl, isoethrine mesylate, isoprenaline, isoproterenol sulfate, isosorbide dinitrate, levallorphan tartrate, levodopa, lidocaine HCl, lignocaine, loratadine, lorcainide, meperidine FIG, 6-mercaptopurine, metaproterenol sulfate, mesalamine, metformin, methoxamine HCl, methylphenidate, methylpreonisolone, methyltestosterone mesylate, metoclopramide, metoprolol tartrate, metoprolol succinate, morphine sulfate, nalbuphine HCl, naloxone HCl, neostigmine, nifedipine, nitrendipine, nitroglycerin, norepinephrine bitartrate, norethindrone, nortriptylene HCl, oxprenolol, omeprazole, oxybutanin, oxycodone, oxyphenbutazone, paroxetine, penicillamine, pentazocine HCl, pentazocine lactate, pentobarbital, petnidine, phenacetin, phentolamine HCl, phentolamine mesydate, phenylephrine HCl, phenylephrine bitartrate, phenytoin, pindolal, prazosin, prednisone, progesterone, propoxyphene HCl, propoxyphene napsylate, propranolol FIG, quinidine, riluzole, reserpine, ritodrine HCl, salicylamide, salbutamol, secobarbital, testosterone, terbutaline, timolol maleate, tolbutamide, venlafaxine or verapamil HCl. The active agent which may be used in the present invention also includes those listed in U.S. Pat. No. 6,024,976, issued Feb. 15, 2000, to Miranda et al.
In another preferred embodiment, the active agent can be isosorbide-5-mononitrate.
In a preferred embodiment, the active agent of the drug delivery can exhibit the following in vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXII at 37xc2x0 C. in deionized water at 75 rotations per minute:
(a) from about 0% to about 90% of said active agent is released between 1 hour and 16 hours of measurement in said apparatus; and
(b) from about 0% to about 100% of said active agent is released between 1.5 hours and 28 hours after measurement in said apparatus.
In another preferred embodiment, the active agent of the drug delivery system can exhibit the following in vitro dissolution profile when measured under the same conditions described above:
(a) from about 10% to about 75% of said active agent is released between 1 hour and 5 hours of measurement in said apparatus; and
(b) no less than about 90% of said active agent is released after 6 hours of measurement in said apparatus.
In yet another preferred embodiment, the active agent of the drug delivery system exhibits the following in vitro dissolution profile when measured under the same conditions described above:
(a) from about 0% to about 50% of said active agent is released after 1 hour of measurement in said apparatus;
(b) from about 0% to about 90% of said active agent is released between 1 hour and 16 hours after measurement in said apparatus; and
(c) from about 0% to about 100% of said active agent is released between 1.5 hours and 28 hours after measurement in said apparatus.
In still another preferred embodiment, the active agent of the drug delivery system exhibits the following in vitro dissolution profile when measured under the same conditions described above:
(a) from about 0% to about 35% of said active agent is released after 1 hour of measurement in said apparatus;
(b) from about 10% to about 90%0 of said active agent is released between 1 hour and 5 hours after measurement in said apparatus; and
(c) no less than 90% of said active agent is released after 6 hours of measurement in said apparatus.
In a preferred embodiment, the active agent exhibiting these dissolution profiles can be isosorbide-5-mononitrate.
The polymers of the drug delivery system can be one or more polymers selected from alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, magnesium stearate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate, starch, ethylcellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polymethacrylates, povidone, shellac, or zein, of which colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and hydroxypropyl methylcellulose are the most preferred.
The hydrophilic polymer can be any hydrophobic polymer which will achieve the goals of the present invention including, but not limited to, one or more polymers selected from carboxymethylcellulose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, or povidone, of which hydroxypropyl methylcellulose is further preferred.
The hydrophobic polymer of the drug delivery system can be any hydrophobic polymer which will achieve the goals of the present invention including, but not limited to, one or more polymers selected from carbomer, carnauba wax, ethylcellulose, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil type 1, microcrystalline wax, polacrilin potassium, polymethacrylates, or stearic acid, of which hydrogenated vegetable oil type 1 is further 5 preferred.
The present invention also accomplishes these and other objectives through a method for preparing a press coated, pulsatile drug delivery system suitable for oral administration including the steps of combining an effective amount of an active agent, or a pharmaceutically acceptable salt thereof, and a polymer to form an immediate-release compartment; combining an effective amount of an active agent, or a pharmaceutically acceptable salt thereof, and a combination of hydrophilic and hydrophobic polymers to form an extended-release compartment; and press coating the extended-release compartment to substantially envelop the immediate-release compartment.
A preferred embodiment further includes the steps of combining an effective amount of an active agent, or a pharmaceutically acceptable salt thereof, and a polymer to form an instant-release compartment, and press coating the instant-release compartment to substantially envelop the extended-release compartment.
In another preferred embodiment, the combining steps can be done by blending, wet granulation, fluid-bed granulation, or dry granulation according to methods recognized the art.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. The detailed description and the specific examples, however, indicate only preferred embodiments of the invention.
Various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.